SK128896A3 - Tropane derivatives, their preparation and application - Google Patents

Abstract

The present invention discloses compounds of formula (I), (II), (III) or (IV) any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; R<3> is CH=NOR', wherein R' is hydrogen or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or alkyl all of which may be substituted with COOH, COO-alkyl, COO-cycloalkyl, or phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro; and R<4> is phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; 3,4-methylenedioxyphenyl; benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or naphthyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl. The compounds possess valuable pharmaceutical properties as monoamine neurotransmitter, i.e. dopamine, serotonine, noradrenaline, reuptake inhibitors.

Description

Tropane derivatives, their preparation and use

Technical field

The invention relates to novel oxime derivatives which inhibit the reuptake of monoamine neurotransmitters, e.g. dopamine, serotonin or noradrenaline. In particular, the present invention relates to novel oxime derivatives which effectively inhibit dopamine reuptake and which, as such, have significant antiparkinsonian, antidepressant, antiobesic, antinarcoleptic and antmarkomanic activity, and which at the same time have few undesirable side effects; it further relates to a process for the preparation of these novel oxime derivatives; pharmaceutical compositions comprising these novel oxime derivatives and a method of treating Parkinson's disease, depression, obesity, narcolepsy and drug abuse by administering a therapeutically effective amount of one or more of the new oxime derivatives to a living animal organism including a human.

BACKGROUND OF THE INVENTION

Dopamine is released into the synaptic cleft to stimulate postsynaptic dopaminergic receptors. Dopamine is removed by re-uptake into presynaptic terminals. By inhibiting this uptake, an increase in physiological dopaminergic activity is achieved. Substances that are capable of inhibiting dopamine reuptake can be expected to be useful in the treatment of Parkinson's disease, depression, cocaine addiction, obesity and narcolepsy.

Cocaine is a well known substance that effectively releases dopamine and at the same time inhibits its reuptake. Cocaine has many pharmacological effects, but in particular it strongly stimulates the CNS and has a local anesthetic effect. These effects are accompanied by its high toxicity and addictiveness (see, e.g., KL. Čarke et al. In Journal of Medicinal Chemistry 16 (11). 1261-1267 (1973)). The cocaine addiction is believed to be related to its potent stimulatory action, short-lived effect and rapid onset of action along with its pronounced dopamine release ability. Substances that are capable of selectively inhibiting dopamine reuptake over a long period of time and which do not have the ability to release dopamine are expected to be

- 2 particularly useful as a new type of antiparkinsonian, antidepressant, anti-obesity and antinarcoleptic agents. Furthermore, these substances will be extremely useful in the treatment of drug addiction, in particular for the treatment of cocaine addiction or abuse.

Over the years, many attempts have been made to optimize the properties of cocaine. Many cocaine derivatives and isomers have been synthesized. Examples can be found in articles published by KL Clarke et spoL in Journal of Medicinal Chemistry 16 (11), 12611267 (1973) and F. Ivy Caroll et spoL in Journal of Medicinal Chemistry 34, 883-886 (1961). Many of these derivatives, but probably in particular those disclosed by KL.Clarke and spoL, are substances with a very potent stimulatory effect, which have been found to be very potent dopamine reuptake inhibitors. However, none of these cocaine derivatives synthesized to date have been found to have no adverse effects. Therefore, the need for new dopamine reuptake inhibitors is still present.

Some of the compounds provided by this invention, in addition to their dopamine reuptake inhibiting properties, are also potent serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. The drugs currently used in the treatment of depression are norepinephrine reuptake inhibitors (desipramine, nortriptyline and protriptyline), or are mixed serotonin and norepinephrine reuptake inhibitors (imipramine and amitriptyline). A serious deficiency of these substances is the delayed onset of their effect (several weeks). It is believed that a mixed serotonin and dopamine reuptake inhibitor may have a more advantageous antidepressant effect with a faster onset of action.

It is an object of the present invention to provide oxime derivatives having antiparkinsonian, antidepressant, antiohesive, antinarcoleptic and antinarcomanic activity.

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It is a further object of the invention to provide novel pharmaceutical compositions comprising novel oxime derivatives which are useful in the treatment of Parkinson's disease, depression, obesity, narcolepsy and drug abuse.

Yet another object of the invention is to provide a method of treating Parkinson's disease, obesity, narcosis and drug abuse by administering a therapeutically effective amount of one or more new oxime derivatives to an organism of an animal, including a human.

Other objects of the invention will be understood by those skilled in the art.

SUMMARY OF THE INVENTION

The invention consists, inter alia, of the following, alone or in combination:

Use of a compound of formula

mixtures thereof, or a pharmaceutically acceptable compound thereof;

where

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl;

R ³ is CH = NOR ', wherein R' is hydrogen or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted with COOH, COO-alkyl, COO-cycloalkyl, or phenyl, which may be substituted once or multiple substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, and nitro; and

R ⁴ is phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

3,4-methylenedioxyphenyl;

benzyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy,

4 alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or naphthyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl, for the manufacture of a medicament for treating a disorder or disease a living animal organism, including a human, that is sensitive to inhibition of monoamine neurotransmitter reuptake in the central nervous system;

use of a compound of formula

mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or 2-hydroxyethyl;

R 6 is CH = NOR ', wherein R' is hydrogen or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted with COOH, COO-alkyl, COO-cycloalkyl, or phenyl, which may be substituted once or multiple substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, and nitro; and

- R ⁴ is phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

3,4 methylenedioxyphenyl;

benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or naphthyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl, to produce a bleaching agent for a disorder or disease a living animal organism, including a human, which is susceptible to inhibiting reuptake of monoamine neurotransmitters in the central nervous system;

use of a compound of formula

mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or 2-hydroxyethyl;

R 6 is CH = NOR ', wherein R' is hydrogen or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted with groups

COOH, COO-alkyl, COO-cycloalkyl, or phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino and nitro; and

R ⁴ is phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

3,4 methylenedioxyphenyl;

benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or naphthyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryhi, for the manufacture of a medicament for treating parkinsonism, depression , obesity, narcolepsy or drug addiction, or drug abuse;

any of the above uses wherein the compound is 3- (3,4-dichlorophenyl) tropan-2-aldoxime

3- (3,4-Dichlorophenyl) tropane-2-O-methyl-aldoxime,

- (3,4-Dichlorophenyl) tropane-2-O-benzylidene-aldoxime,

- (3,4-Dichlorophenyl) tropane-2-O-ethoxycarbonylmethyl-aldoxime,

3- (3,4-Dichlorophenyl) tropane-2-O-aldoxime metoxykarhonylmetyl,

- (3,4-Dichlorophenyl) tropane-2-O- (1-ethoxycarbonyl-1,1-dimethylmethyl) -aldoxime,

7- 3- (3,4-dichlorophenyl) tropane-2-O-carboxymethyl-2-aldoxime, N-normethyl-3- (3,4-dichlorophenyl) tropane-2-O-methyl-aoxoxime or N-normethyl- 3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxime, or a pharmaceutically acceptable addition salt thereof;

any of the above uses wherein the compound used is (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropan-2-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane -2-O-benzyl-aldoxime (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-ethoxycarbonylmethyl-aldoxime, (1R, 2R, 3S) -3- (3,4- dichlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O- (1-ethoxycarbonyl-1,1-dimethylmethyl) aldoxime (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-carboxymethyl-2-aldoxime, (1R, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime or (1R, 2R, 3S) -N-normethyl-3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxime, or a pharmaceutically acceptable addition salt thereof;

any of said uses, wherein the compound used is (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime or a pharmaceutically acceptable addition salt thereof;

any of the above uses wherein the agent is the (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime anti-isomer, the syn-isomer (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime, a mixture thereof, or a pharmaceutically acceptable addition salt thereof;

compound of formula

any mixture thereof, or a pharmaceutically acceptable salt thereof;

- 8 where

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or 2-hydroxyethyl;

R-3 is CH = NOR ', wherein R' is hydrogen or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted by COOH, COO-alkyl, COO-cycloalkyl, or phenyl, which may be substituted one or more substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino and nitro; and

R ⁴ is phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

3,4 methylenedioxyphenyl;

benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

naphthyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

a compound that is

3- (3,4-dichlorophenyl) tropan-2-aldoxime 3- (3,4-dichlorophenyl) tropan-2-O-methyl-aldoxime, 3- (3,4-dichlorophenyl) tropane-2-O-benzyl- aldoxime,

- 9 3- (3,4-Dichlorophenyl) tropane-2-O-ethoxycarbonylmethyl-aldoxime,

- (3,4-Dichlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime,

- (3,4-dichlorophenyl) tropane-2-O- (1-ethoxycarbonyl-1,1-dimethylmethyl) -aldoxime, 3- (3,4-dichlorophenyl) tropane-2-O-carboxymethyl -2-aldoxime, N-normethyl-3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime or N-normethyl-3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxime , or an icb pharmaceutically acceptable addition salt;

(1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane- 2-Benzyl-aldoxime (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-ethoxycarbonylmethyl-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2- (1-ethoxycarbonyl-1,1-dimethylmethyl) aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-carboxymethyl-2-aldoxime, (1R, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) tropane- 2-O-methyl-aldoxime or (1K2R, 3S) -N-normethyl-3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxime, or a pharmaceutically acceptable addition salt thereof;

(1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime, or a pharmaceutically acceptable addition salt thereof;

a substance which is the anti-isomer of (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime, the syn-isomer of (1R, 2R, 3S) -3- (3 (4-dichlorophenyl) tropane-2-O-methyl-aldoxime, a mixture thereof, or an icb pharmaceutically acceptable addition salt;

a process for the preparation of any of said compounds, comprising the step of reacting a compound of formula its enantiomers or mixtures thereof, wherein R is as defined above and is a carboxylic ester, or wherein R 1 denotes a substituent within the meaning of the above definition of R ³ ;

R ⁴ -A, wherein R ⁴ is as defined above and A is any type of reactive group suitable for forming a carbanion as its counterpart, such as e.g. Li, MgX, wherein X is halogen, and CuLi, in a reaction similar to a Michael addition reaction of 1,4, and wherein if R L2 j _e a carboxylic ester, and converting the compound obtained to those described invention using conventional methods;

a pharmaceutical composition comprising an effective amount of any of the foregoing or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier or diluent;

a method of treating a disorder or disease of a living animal organism, including a human, whose disorder or disease is susceptible to inhibiting dopamine uptake, comprising administering to said animal organism, including a human, an effective amount of a compound of the formula

any mixture thereof, or a pharmaceutically acceptable reindeer thereof;

where

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl;

R ³ is CH = NOR ', wherein R' is hydrogen, or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted with COOH, COO-alkyl or COO-cycloalkyl or phenyl, which may be substituted once or multiple substituents selected from the group consisting of halogen,

11 CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino and nitro; and

R ⁴ is phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

3,4-methylenedioxyphenyl;

benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;

heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or naphthyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; and a treatment method for treating parkinsonism, depression, obesity, narcolepsy or drug addiction and / or drug abuse.

Examples of pharmaceutically acceptable addition salts include additive salts of inorganic and organic acids, e.g. hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleic, fumaran, mandelan, benzoate, ascorbate, cinnamon, benzosulfonate, methanesulfonate, stearate, succinate, glutamate, glycolate, toluene-p-sulfonate, malonate, naphthalene-2-sulfonate, salicylate and acetate. Such salts are formed by generally known methods.

Other acids, although not in themselves pharmaceutically acceptable, e.g. oxalic acid may be useful in the preparation of reindeer compounds useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable reindeer compounds.

Halogen is fluorine, chlorine, bromine or iodine.

Alkyl means a straight chain or branched chain of one to six carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl, with methyl, ethyl, propyl and isopropyl

Cycloalkyl means a cyclic alkyl of three to seven carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

Alkenyl means a group of two to six carbon atoms having at least one double bond, for example, but not exclusively, ethenyl, 1,2- or 2,3-propenyl, 1,2- 2,3- or 3,4-butenyl.

Alkynyl means a group of two to six carbon atoms having at least one triple bond, for example, but not exclusively, ethynyl 2,3-propynyl, 2,3- or 3,4-butynyl.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, e.g. cyclopropylmethyl

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Cycloalkoxy is O-cycloalkyl, wherein cycloalkyl is defined as above.

Amino is NH 2, or NH-alkyl, or N- (alkyl) 2, wherein alkyl is defined as above.

Heteroaryl is preferably a 5- or 6-membered heterocyclic monocyclic group. Such a heteroaryl group includes e.g. oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol- 5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,

1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl,

1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,

4-pyridyl

Aryl is an aromatic hydrocarbon, e.g. phenyl and naphthyl

Ip means intraperitoneal, which is a well-known route of administration.

After. means orally, which is a well-known method of administration of substances.

Further, the compounds described in this invention may exist in both insoluble and soluble forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Soluble forms are generally considered equivalent to insoluble forms for the purposes of the invention.

One skilled in the art will appreciate that the compounds described in this invention have several chiral centers and that such compounds exist in the form of isomers (i.e., enantiomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures

Some of the compounds of the present invention exist in (+) and (-) as well as in racemic forms. Racemic forms can be resolved into optical antipodes by known methods, e.g. separating their diastereoisomeric salts with an optically active acid and liberating the optically active amine compound with a base. Another method for separating racemates into optical antipodes is based on their chromatography on an optically active matrix. Thus, the racemic compounds of the present invention can be divided into optical antipodes e.g. by fractional crystallization of their d- or 1- salts (e.g., tartrate, mandelate or camphrosulfonate). The compounds of the present invention are:

14 can be resolved by formation of diastereoisomeric amides by reacting the compounds of this invention with an optically active activated carboxylic acid, e.g. derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanoic acid, or by forming diastereoisomeric carbamates by reacting the compounds of the invention with optically active chloroformate and the like.

Other generally known methods known to those of ordinary skill in the art can also be used for resolving optical isomers. Such methods include those described by J. Jacques, A. Collet and S. Wilen in Enantiomers, Racemates, and Resolutions, eds. John Wiley &amp; Sons, New York (1981).

Moreover, since the compounds of the invention are oximes, they may exist in two forms, syn- and anti-, depending on the arrangement of substituents around the -C = N- double bond. The present invention covers both the syn- and anti-form of the compounds described by the invention, as well as mixtures thereof. Acids catalyze anti-syn isomerization.

The compounds of the invention may be prepared in a number of ways. Thus, the compounds of the invention and their pharmaceutically acceptable derivatives can be prepared by any method known for the preparation of compounds of analogous structure and as shown by the representative examples that follow.

DETAILED DESCRIPTION OF THE INVENTION

The following scheme illustrates the method by which the compounds of the invention can be prepared:

M

(I)

H H (1R, 2S, 3S) (1R, 2R, 3S) cis-form trans-form

In this reaction scheme, A denotes any kind of reactive group suitable for forming a carbanion as its counterpart, such as e.g. Li, MgX, where X is halogen and CuLi in a Michael-like reaction of type 1,4, R 12 is a carboxylic ester, e.g. COO-Me, COO-Et and COO-iPro, or is r ³ as defined above and wherein R and R ⁴ are as defined above.

Reaction of a compound of formula (i). with the R ⁴ -A according to the equation described above, both the cis-form and the trans-form and mixtures thereof can be obtained, but the compounds obtained are almost exclusively substances in which the R ⁴ substituent is in the equatorial position.

Isomerization of the cis-isomer to the trans-isomeric form may be affected by a strong base, e.g., an alcoholate.

The enantiomers of cis- and trans-compounds in the above scheme can be obtained by the same procedure and using the enantiomer of the compound of formula (i):

(iv) as starting material.

Racemic mixtures of cis- and trans- compounds can be obtained using a mixture of compounds of formulas (i) and (iv) as starting material.

The compounds obtained by above-mentioned method, wherein R L2 j _e a carboxylic ester may be converted to the compounds which are the subject of the invention, using conventional methods involve the reduction of metód.Takéto 2-carboxylic ester to 2-hydroxymethyl followed by further oxidation to the corresponding 2-aldehyde. The oxides of the invention can then be obtained by reacting the 2-aldehyde with hydroxylamine derivatives of NH 2 -OR ', where R' is as defined above:

The compound of the invention can be converted to another compound of the invention by conventional methods.

The starting materials of the reactions described in this patent application are known or can be prepared by reactions of commercially available materials.

Thus, the starting materials of formula (i), wherein R ² is a carboxylic ester, can be obtained from cocaine by conventional methods, i. as described in the following examples.

The starting materials of formula (i), wherein R ² is oxime, can be prepared by the same procedure as described above for the preparation of oximes of the invention and as described in EP-A2-316718.

The reaction products described herein are isolated by conventional methods such as e.g. extraction, crystallization, distillation, chromatography and the like.

biology

The compounds of the present invention were tested for their ability to bind to the dopamine transporter in the following assays to inhibit ³ H-WIN 35428 binding in vitro and in vivo.

- 17 Inhibition of @ 1 H-WIN 35428 binding in vitro

essence:

Dopamine carriers, respectively. dopamine uptake sites in the nerve endings are likely to terminate neural signaling by removing dopamine from the synaptic cleft. The activity or presence of an integral dopamine transporter protein can be measured in vitro by uptake of ^H-dopamine into synaptosomes or by binding of HH-ligands known to bind to the transporter.

Cocaine binding studies have shown that cocaine binds to the dopamine transporter and inhibits the uptake of ^H-dopamine. Numerous ligands with different structures have been found to bind to the dopamine uptake site, but it is still unclear in the

whether their binding sites are identical to the sites to which cocaine binds. The structural analog of cocaine HH-WIN 35428 binds selectively and with high affinity to the dopamine transporter complex.

Tissue preparation:

Preparations are prepared at 0-4 ° C unless otherwise noted. Coipus striatum, prepared from the brain of male Wistar rats (150-200 g), is homogenized for 5-10 seconds in 10 ml NaH 2 PCO 4 (50 mM, pH 7.4) using an Ultra-Turrax homogenizer. The suspension is centrifuged at 27,000 x g for 15 min. The supernatant was discarded, the pellet was resuspended in 50 mM Na 2 PO 2, pH 7.4 (1000 ml per 1 g of original tissue) and used for binding studies.

determination:

Aliquots of 0.5 ml tissue are added to 25 ml of assay solution and 25 ml of 1 H-WIN 35428 (1 nM final concentration), mixed and incubated for 60 min at 2 ° C. Non-specific binding is determined by cocaine (30 mM final concentration). After incubation, 5 ml of ice buffer solution is added to the samples and the samples are poured directly onto a Whatman GF / C glass fiber filter under suction, rinsing immediately with 5 ml of ice buffer solution.

The amount of radioactivity on the filter is determined by conventional liquid scintillation spectrophotometry. Specific binding is expressed by subtracting non-specific binding from total binding.

25-75% inhibition of specific binding must be obtained before IC 50 calculation. The measured value is expressed as IC 50 (i.e., that concentration of test substance expressed in mM that inhibits the specific binding of 3H-WIN 35428 by 50%).

Inhibition of ³ H-WIN 35428 Binding In Vivo

essence:

Ligand ³ H-WIN 35428 can also be used in in vivo studies of receptor labeling in mice. The accumulation of ³ H-WIN 35428 occurs mainly in areas of the brain that contain dopaminergic nerve endings. The striatum which contains the highest concentration of dopamine has the highest accumulation of 3 H-WIN 35428. The specific binding in the striatum reaches a maximum 30 min after IV administration of ³ H-WIN 35428 and this maximum is maintained for another 30 minutes. This specific ³ H-WIN 35428 binding can be prevented by the simultaneous or prior administration of agents known to inhibit dopamine transport and ligand binding to the dopamine transport complex, i.e., GBR 12909, cocaine and nomifensin (Scheffel et al., J Pharm. Exp. Ther., 257. 954-958 (1991).

All test substances are solutions or suspensions prepared in 10% TWEEN e 80. Mice, female NMRI strain (25 g), divided into groups of 3, are injected with test substance Ip. Immediately after this injection, mice are injected into the tail vein with 2.0 mCi of ³ H-WIN 35428 in 0.2 ml saline. Forty-five minutes after ³ H-WIN 35428 administration, mice are sacrificed by decapitation and the corpora striatum is rapidly dissected on ice. The tissue is weighed and dissolved in 1 ml of 2% Na-lauryl sulfate over 36 hours. The solubilized tissue is then added to 2 ml of scintillation cocktail and the amount of radioactivity per mg of tissue is determined by conventional liquid scintillation spectrophotometry. Groups of unmedicated mice serve as controls. To determine non-specific binding, groups of mice are injected with WIN 35428 (2.5 mg / kg) ip. at the same time

- 19 injection of ³ H-WIN 35428. The specific binding is the amount of binding in controls minus the amount binding in mice was administered MAC 35428th

The ED 50 value is determined from a dose-response curve. If only one dose of the test substance is administered and the specific binding inhibition is in the range of 25-75%, the ED5Q is calculated as follows:

ED 50 = (dose administered in mg / kg) x 1 / (C ₀ / C _X - 1), where C _o is specific binding in controls and C _x is specific binding in mice receiving test substance.

The results obtained with the test compounds according to the invention are shown in Table 1:

- 20 Table 1

test substance in vivo ED ₅₀ (mg / kg) in vitro IC ₃₀ mM (R, 2 R, 3 S) -3- (3,4-dichlorophenyl) - tropane-2-O-methyl-aldoxŕm, H.SO. 0.9 0.0030 (R, 2 R, 3 S) -3- (3,4-dichlorophenyl) - tropane-2-aldoxime 3.8 0.0034 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-benzyl-aldoxime, HCl > 10.00 0.0760 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-ethoxycarbonylmethylaldoxime, HCl > 10.00 0,024 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-aldoxime 0.56 0.0020 (1R, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) -tropane-2-O-methylaldoxime, HCl 1.4 0,006 (R, 2 R, 3 S) -3- (4-chlorophenyl) - tropane-2-aldoxlm 1.05 0,013 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O- (2-propynyl) aldoxime, HCl amp; 0,019 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O- (2-propenyl) aldoxime, HCl amp; 0,022

test substance in vivo ED ₅₀ (mg / kg) in vitro IC ₅₀ μΜ (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-O- (2-methylpropyl) aldoxime, HCl amp; 0,056 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-cyclopropylmethylaldoxime, HCl amp; 0.02 (1R, 2R, 3S) -3- (4-Methylphenyl) tropane-2-O-methyl-aldoxone, HCl amp; 0,042 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-methyl-aldoxime, HCl 0.37 0.0018 (1R, 2R, 3S) -3- (4-chlorophenyl) tropane-2-O-methyl-aldoxime, HCl 1.0 0,048

amp; = not tested

The test results show that the compounds of the invention bind with high affinity to the dopamine transporter complex under both in vitro and in vivo conditions.

The compounds of the present invention were also tested for their ability to inhibit dopamine (DA), noradrenaline (NA) and serotonin (5-HT) reuptake into synaptosomes.

essence:

Specific neurotransmitter transporters / sites of uptake in nerve endings are likely to terminate neuronal signaling by removal

-22 neurotransmitter of dopamine, noradrenaline or serotonin from the synaptic cleft. The activity of integral transporter proteins can be measured under in vitro conditions by uptake of ³ H-dopamine, ³ H-noradrenaline or ³ H-serotonin into synaptosomes.

Inhibition of ³ H-dopamine ( ³ H-DA) uptake into striatal synaptosomes in vitro

Tissue preparation:

Preparations are prepared at 0-4 ° C unless otherwise noted. The striatum corpora isolated from male Wistar rats (150-200 g) are homogenized for 5-10 seconds in 100 volumes of 0.32 M ice sucrose containing 1 mM pargylline using an UltraTurrax homogenizer. Monoamine oxidase activity is inhibited in the presence of pargylline. The homogenate is centrifuged at 1000 x g for 10 min. The supernatant obtained is then centrifuged at 27,000 x g for 50 min and the supernatant discarded. The pellet (P2) is resuspended in oxygenated (equilibrated with an atmosphere containing 96% O 2 and 4% CO 2 for at least 30 min) with a Krebs-Ringer incubation buffer (8000 ml per gram of original tissue) at pH 7.2 containing 122 mM NaCl 0.16 mM EDTA,

4.8 mM KCl, 12.7 mM Na 2 HPO 4, 3.0 mM Na 2 PO 2, 1.2 mM MgSO 4, 1 mM CaCl 2, 10 mM glucose and 1 mM ascorbic acid.

The determination;

Aliquots of 4 ml tissue suspension are added to 100 ml test solution and 100 ml ³ H-DA (final concentration 1 nM), mixed and incubated for 25 min at 37 ° C. Non-specific uptake is determined by benztropine (final concentration 10 mM). After the samples are incubated, the samples are poured directly onto Whatman GF / C glass fiber filters and pre-sucked under suction. The filters are then washed three times with 5 ml of 0.9% (w / v) ice-cold NaCl solution. The amount of radioactivity on the filter is determined by conventional liquid scintillation spectrophotometry. Specific uptake is calculated as the difference between total and non-specific uptake.

25-75% specific binding inhibition must be obtained before calculating the IC 50 value.

The measured value is expressed as IC 50 (concentration of test substance expressed in mM at which the test substance inhibits specific binding of HH-DA by 50%).

Inhibition of HH-noradrenaline uptake (HH-NA) into hippocampal synaptosomes in vitro

Tissue preparation:

Preparations are prepared at 0-4 ° C unless otherwise noted. Hippocamps isolated from male Wistar rats (150-200 g) are homogenized for 5-10 seconds in 100 volumes of 0.32 M ice sucrose containing 1 mM pargyline using an Ultra-Turrax homogenizer. Monoamine oxidase activity is inhibited in the presence of pargyline. The homogenate is centrifuged at 1000 x g for 10 min. The supernatant obtained is then centrifuged at 27,000 xg for 50 min and the supernatant discarded. The pellet (P2) is resuspended in oxygenated (equilibrated with an atmosphere containing 96% O2 and 4% CO2 for at least 30 min) with a Krebs-Ringer incubation buffer (2000 ml per gram of original tissue) at pH 7.2 containing 122 mM NaCl 0.16 mM EDTA, 4.8 mM KCl, 12.7 mM Na ₂ HPO ₄ , 3.0 mM NaH ₂ PO ₄ , 1.2 mM MgSO ₄ , 0.97 mM CaCl 2, 10 mM glucose and 1 mM ascorbic acid.

determination:

Aliquots of 4 ml of tissue suspension are added to 100 ml of test solution and 100 ml of 1 H-NA (1 nM final concentration), mixed and incubated for 90 min at 37 ° C. Non-specific uptake is determined by desipramine (1 mM final concentration). After incubation of the samples, samples are poured directly onto Whatman GF / C glass fiber filters and filtered under suction. The filters are then washed three times with 5 ml of a 0.9% (w / v) ice-cold NaCl solution. The amount of radioactivity on the filter is determined by conventional liquid scintillation spectrophotometry. Specific uptake is calculated as the difference between total and non-specific uptake.

25- 25% -75% inhibition of specific binding must be obtained before calculating the IC 50 value.

The measured value is reported as IC 50 (concentration of test substance in mM at which the substance inhibits specific binding of ^H-NA by 50%).

Inhibition of β-5-hydroxytryptamine ( ³ H-5-HT, serotonin) uptake into cortical synaptosomes in vitro

Tissue preparation:

Preparations are prepared at 0-4 ° C unless otherwise noted. Brain cortex isolated from male Wistar rats (150-200 g) is homogenized for 5-10 seconds in 100 volumes of 0.32 M ice sucrose containing 1 mM pargyline using an Ultra-Turrax homogenizer. Monoamine oxidase activity is inhibited in the presence of pargyline. The homogenate is centrifuged at 1000 x g for 10 min. The obtained scaffold is then centrifuged at 27,000 x g for 50 min and the scaffold is discarded. The pellet (P2) is resuspended in oxygenated (equilibrated with an atmosphere containing 96% O2 and 4% CO2 for at least 30 min) with a Krebs-Ringer incubation buffer (1000 ml per gram of original tissue) at pH 7.2. which contains 122 mM NaCl, 0.16 mM EDTA,

4.8 mM KCl, 12.7 mM Na 2 HPO 4, 3.0 mM NaH 2 PO 4, 1.2 mM MgSO 4, 1 mM CaCl 2, 10 mM glucose and 1 mM ascorbic acid.

determination:

Aliquots of 4 ml of tissue suspension are added to 100 ml of test solution and 100 ml of Η-5-ΗΤ (final concentration 1 nM), mixed and incubated for 30 min at 37 ° C. Non-specific uptake is determined with citalopram (1 mM final concentration). After incubation, samples are poured directly onto Whatman GF / C glass fiber filters and filtered under suction. The filters were then washed three times with 5 ml of 0.9% (w / v) NaCl ice solution. The amount of radioactivity on the filter is determined by conventional liquid scintillation spectrophotometry.

Specific uptake is calculated as the difference between total and non-specific uptake.

25-75% inhibition of specific binding must be obtained before calculating the IC 50 value.

The measured value is reported as IC 50 (concentration of test substance in mM at which the substance inhibits specific binding of ³ H-5-HT by 50%).

The test results obtained with selected compounds of the present invention are shown in the following table:

Table 2

test substance uptake DA Κ _Μ (μΜ) uptake to IC ₅₀ (pM) 5-HT IC ₅₀ uptake (pM) (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) -tropane-2-O-methyl-aldoxime, 0,003 0.0013 0,013 (1R, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) tropan-2-O-methylaldoxime, HCl 0,002 0.0013 0.0017 (R, 2 R, 3 S) -3- (3,4- dichlorophenyl) tropane-2-O methyl-aldoxime, syn-isomer 0.0034 0.0015 amp;

amp; = not tested

The results show that the test substances effectively suppress re-uptake; dopamine, norepinephrine, and serotonin to synaptosomes.

The compounds of the present invention have also been tested in the following animal models of Parkinson's disease.

MPTP induced parkinsonism in tailed monkeys (Callitricidae)

essence:

Administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium hydrochloride) to monkeys causes impairment of the dopaminergic system in the brain and causes symptoms of parkinsonism. Upon subsequent administration of the test substances, their ability to attenuate the symptoms of parkinsonism can be ascertained.

method:

Common tailed monkeys (Marmoset Monkeys, Callitricidae) weighing 350-400 g at the age of 3-5 years, regardless of sex, were used in the study. The cane animals are housed separately under standard conditions at 25-27 ° C and 50% relative humidity, maintaining a 12 hour light-dark cycle.

Animals had free access to food and water.

A few months prior to the start of locomotion and behavior testing, the animals received MPTP (1-methyl-4-phenyl-1,2,3,6-terahydropyridinium hydrochloride) dissolved in sterile saline (0.9% NaCl) at dose 2 mg / kg subcutaneously for 5 days, but until they have developed a clear parkinsonian condition. The cumulative dose was between 8-12 mg / kg. During MPTP administration and over the next 2-3 weeks, the animals were fed by hand until they recovered enough to feed themselves. Prior to behavioral testing, all animals experienced significant reductions in basal locomotor activity, decreased head scans and abnormal spine, but especially limb position.

Test substances were dissolved in 100% Tween 80 heated to 40-50 ° C. Then they were diluted in water. Test substances were administered by oral gavage in a volume of 2ml / kg. To compare the effect of the test substances, in a supplemental experiment, vehicle was administered on each experimental day. Each animal is given in the coming weeks

- 27 administered the vehicle, or one of three doses of test substances with a one week interval between administrations.

Weakness rating:

Weakness of the animals was evaluated as follows: consciousness (normal 0, drowsiness 2), irritation response (normal 0, diminished 1, slow 2, absent 3), viewing movements (present 0, diminished 1, absent 2), attention and eye movements ( normal 0, abnormal 1), posture (normal 0, abnormal torso position 1, abnormal limb position 1, tail abnormal position 1 or overall abnormal p 4), balance and coordination (normal 0, damaged 1, unstable 2, spontaneous falls 3) , vocalization (normal 0, diminished 1, absent 2).

Measurement of locomotor activity:

Locomotor activity was measured simultaneously in four animals, each of which was housed separately in a metal cage (50 x 60 x 70 cm - width, length, height) with a transparent plastic door (50 x 70 cm - width, height), which resembled breeding cages, but in which eight horizontally placed infrared photocells were built. Their rays were placed at floor level, across the cage, and one was oriented along each of the two perches. Other rays pointed from the front wall to the rear wall of the cage at the floor level and above the level of each perch. Locomotor pulses were calculated as the number of rays interrupted by the movement of the animal. These pulses were shunted over 30-minute intervals and recorded during a 10-hour experiment.

Data analysis:

For the time courses and the accumulated number of locomotive pulses, the mean with mean diameter error (± S.E.M) in each group was calculated.

The results obtained with the test compound of the invention (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime (NS 2214) are shown in Fig. 1a. the compound of the present invention in a dosage range of from 0.1 to

- 28 2.5 mg / kg, in a dose-dependent manner, increases motor activity and diminishes scores that indicate motor disability.

The compounds of the invention were also tested in the following antidepressant activity test.

Curtain behind the tail

essence:

Following systemic administration of central stimulants and antidepressants, a shortening of immobility can be observed in tailed mice (Steru, L., Cheimat, R., Thieriy, B. and Simon, P. (1985). , Psychopharmacology 85: 367-370.).

method:

NMRI mice, female (20-25 g), which were habituated to the space (12 hour light / dark cycle) for at least 16 hours and which were placed in groups of 25 individuals per cage, were used in the assay. Mice were hung for 30 min with adhesive tape at the tail of a rod placed 30 cm above the laboratory table after being administered orally by vehicle or substance. Over the next 6 min, the accumulated duration of immobility defined as the absence of torso or limb movements was measured (but head movements were not defined as movements). Six animals were used to test a single dose.

In mice receiving saline or vehicle, the immobility scores ranged between 160-180 s on average. The ED 50 value was expressed by graphical interpolation of at least 3 doses as a dose that reduced immobility to 100 s.

The following Table 4 presents the results obtained with several substances according to the invention:

- 29 Table 4

test substance ÉD _S0 (mg / kg) (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropan-2-aldoxime 0.41 (1R, 2R, 3S) -3- (3,4-dichlorophenyl) -tropan-2-O-methylaldoxime, 0.1 (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-benzyl-aldoxime, HCl 2 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime 0.25 (1R, 2S, 3S) -3- (3,4-dichlorophenyl) tropan-2-aldoxime 0.27 (R, 2 R, 3 S) -3- (3,4-Dichlorophenyl) tropane-2-O (2-propenyl) -aldoxime 0.23 (1R, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime, HCl 0.95 (R, 2S, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-methyl- aldoxime 0.4

test substance; ED ₅₀ (mg / kg) (1R, 2S, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxime, HCl 0.94 (1R, 2R, 3S) -3- (4-chlorophenyl) tropan-2-aldoxime 0.19 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-O (2-propynyl) aldoxime 0.04 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-ocyclopropylmethyl-aldoxime 0.7 (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropan-2-O (2-methylpropyl) aldoxime 0.8 (1R, 2R, 3S) -3- (4-chlorophenyl) tropan-2-O-methylaldoxime, HCl 0.43

The results shown in the above table predict significant anti-depressant activity of the compounds of the invention.

Side effect profile of the substances according to the invention

Side effects of cocaine and amphetamine derivatives with central stimulatory action include centrally related arousal and stimulation in animals, including primates, and these effects can also be seen in humans. Serious side effects of cocaine and amphetamine derivatives include the ability to cause toxic psychotic

Symptoms reminiscent of mental illness schizophrenia, including hallucinations, paranoia, and abnormal bizarre stereotyped mental activity and stereotyping.

Recent evidence is very likely to indicate and suggest that these symptoms are due to the extensive and massive release of dopamine in the striatal complex, and especially in the mesolimbic dopaminergic system, which innervates limbic structures including nucleus accumbens, in primates and humans.

Thus, the induction of sterotypic abnormal behavior in rodents is one of the most commonly used animal schizophrenia models suitable for testing the action of antipsychotic neuroleptic agents (including haloperidol and chlorpromazine).

The development of toxic abnormal stereotypic amphetamine syndrome, as described below, makes it possible to predict the undesirable toxic central stimulatory effect of dopamine releasing agents in humans.

Classification of abnormal stereotyped behavior

In general, abnormally stereotyped behaviors can be divided into sterotypic behaviors with low and high intensity scores after administration of amphetamine and cocaine-type central stimulants. Stereotyping with a low intensity score includes abnormal and sustained repetition of locomotion, hindlimb erection, sniffing. These syndromes can usually only be seen after lower doses of dopammergic central stimulants, or they can be observed during the initial phase and during the response to high-dose effects. Effects on low intensity behavior are included here in locomotor and erection syndrome.

High intensity stereotyping syndrome is considered here if the behavioral repertoire of the rat is severely limited in variability and if it consists of a continuous repetition of one or only a few types of behavior.

- 32 The stinging-stereotyping syndrome is thus produced only permanently in a small, limited area of the cage. This activity usually begins at the top of the wall and, after administration of the substances at higher doses, the intensity of sniffing towards the bottom of the cage on the wall or on the floor wires increases. At this stage of high intensity stereotyping, all normal elements of behavior are absent, including food intake, drinking, cleansing, and normal exploratory investigations into the environment.

In rats, high intensity nose-to-nose can develop up to nose-licking, resp. even with biting and chewing of the wire cage strings, which occurs after administration of even higher doses of stimulants. The rats then usually sit in a typically hunched position in the corner of the cage. Occasionally backward locomotion can be observed, we reverse.

The following scale is used to assess high intensity stereotypes, provided that the behavioral syndromes are as mentioned above:

+ - only stereotyped nudging ++ = stereotyped nudging and occasional licking +++ = permanent licking associated with gnawing and chewing

Table compound dose (p.o.) efficacy of (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-O-methyl-aldoxime 15 mg / kg +++

The 15 mg / kg dose is the lowest dose that causes this activity.

Pharmaceutical compositions

While it is possible for the treatment of a compound of the invention to be administered as a clear chemical, it is recommended that the active ingredient be administered as a pharmaceutical dosage form.

Accordingly, the invention further provides pharmaceutical dosage forms comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, or derivatives thereof

33 together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and, optionally, prophylactic ingredients. The carrier or carriers must be acceptable in the sense of being compatible with the other ingredients of the dosage form and not deleterious to the user.

Pharmaceutical forms are those forms of the drug which are suitable for administration orally, rectally, nasally, topically (including buccal and sublingual), vaginally, or parenterally (including intramuscular, subcutaneous and intravenous), or in a form suitable for administration by inhalation or insufflation. .

Thus, the compounds of the invention together with a conventional adjuvant, carrier or diluent can be used to prepare the pharmaceutical form and dosage units thereof, and in such form can be used as a solid preparation, e.g. tablets, resp. filled as capsules, as liquids, e.g. solutions, suspensions, emulsions, elixirs, or as capsules filled with these fluids All of these forms can be used for oral use, in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral use, including subcutaneous administration. Such pharmaceutical forms and unit dosage forms may contain conventional components in conventional proportions with or without other additional active ingredients or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredients corresponding to the range of anticipated daily doses. Thus, an appropriate representative unit dosage form is one containing 10 (ten) milligrams of active ingredient, or more generally, from 0.1 to one (100) milligrams per tablet.

The compounds of the present invention may be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to one skilled in the art that the following dosage forms may contain as an active ingredient a compound of the present invention or a pharmaceutically acceptable salt of a compound of the present invention.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be in solid or liquid form. Solid preparations include powders, tablets, pills, capsules, capsules, suppositories and dispersible

- 34 granules. The solid carrier may consist of one or more substances which may also act as solvents, flavoring agents, sohibilizers, lubricants, excipients, binders, preservatives, tablet disintegrating agents, or as a capsule coating material.

In powders, the carrier is a finely divided solid which forms a mixture with the finely divided active component.

In tablets, the active ingredient is mixed in sufficient proportions with a carrier having the necessary binding ability, the tablet being shaped to the desired shape and size.

The powders and tablets preferably contain from five or ten to about seventy percent of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, light wax, cocoa butter and the like. The term preparation is intended to include the dosage form (formulation) of the active ingredient with the capsule-coating material as a carrier, provided that the capsule in which the active ingredient is, with or without carriers, is surrounded by a carrier so attached to it. Similarly, capsules and medicated candies are included. As solid dosage forms suitable for oral administration, tablets, powders, capsules, pills, capsules and medicated candy may be used.

In the preparation of suppositories, the wax, e.g. a mixture of fatty acid glycerides or cocoa butter and the active ingredient is dispersed uniformly therein e.g. stirring. The molten homogeneous mixture is then poured into conventional appropriately shaped molds, allowed to cool until solidified.

Dosage forms suitable for vaginal administration may be e.g. pessaries, tampons, creams, pastes, foams or sprays containing, in addition to the active ingredient, well-known suitable carriers.

Liquid dosage forms may be solutions, suspensions, and emulsions, e.g. water or mixtures of water and propylene glycol. For example, parenteral injectable liquid preparations may be formulated as solutions in aqueous polyethylene glycol solution.

Thus, the compounds of the present invention may be formulated for parenteral administration (e.g., by injection in the form of an injection brew or by continuous infusion) and may be prepared in unit dosage form in ampoules, pre-filled syringes, low-volume infusions or multidose containers with preservatives. The pharmaceutical preparations may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain other formulation components, e.g. auxiliary, stabilizing or dispersing agents.

F

Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of a sterile solid or by lyophilization of a solution, and mixed with a suitable vehicle, e.g. with sterile, pyrogen-free water.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and, if necessary, adding suitable colorants, flavoring agents, stabilizing and diluents.

Aqueous solutions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with a viscous material such as e.g. natural or synthetic gums, resins, methylcehilose, sodium carboxymethylcehilose, or other generally known suspending agents.

Also included are solid formulations which are expected to convert to liquid dosage forms for oral administration just prior to use. Such preparations are solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial or natural sweeteners, dispersants, diluents, solubilizers and the like.

For topical application to the skin, the compounds of the invention may be formulated as ointments, creams or lotions, or as transdermal patches. Ointments and creams may, for example, be formulated in an aqueous or oily base by the addition of suitable

- 36 diluting but gelling agents. The lotions may be formulated in an aqueous or oily base and will generally contain one or more emulsifiers, stabilizers, dispersants, suspending agents, diluents, or coloring agents.

Dosage forms suitable for topical administration in the mouth are medicated sugars (lozengens), which consist of an active ingredient in a flavoring base, usually sucrose and white acacia or tragacanth; pastilles consist of the active ingredient in an inert base, f

e.g. in gelatin and glycerin or in sucrose and acacia. Mouthwashes consist of the active ingredient in a suitable liquid carrier

Solutions of its suspension are applied directly to the nasal cavity by conventional means, e.g. with a dropper, pipette or spray. The dosage forms may be provided in single or multi-dose form. In the latter case, the patient may dispense a suitable, predetermined volume of the solution or suspension using a dropper or pipette. When using a spray, this dosing can be achieved by using a metered spray spray pump.

Administration to the respiratory system can be achieved by an aerosol dosage form in which the active ingredient is provided by a pressurized container with a suitable propellant such as e.g. a chlorofluorocarbon (CFC) such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may advantageously also contain a surfactant, e.g. lecithin. The dose of the substance can be controlled by means of a metering valve.

Alternatively, the active ingredients may be provided in the form of a dry powder, e.g. a powder mixture of a substance with a powder base which may be lactose, starch, starch derivatives, e.g. hydroxypropylmethylcellulose; and polyvinylpyrrolidone (PVP). The powder carrier may advantageously form a gel in the nasal cavity. Mixtures of powders may be administered in unit dosage form, e.g. as capsules or cartridges e.g. of gelatin, or in a blister pack from which the powder may be administered by means of an inhaler.

In administration forms intended for administration to the respiratory system including intra-nasal administration forms, the particles of the substance will generally be small, e.g. about 5 microns or less. Particles of this size can be obtained by known means, e.g. micronization.

If desired, dosage forms adapted for the sustained release of the active ingredient may also be employed.

Pharmaceutical compositions in unit dosage form are preferred. In this case, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as e.g. packaged tablets, capsules and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, capsule or medicated candy per se, or it may be an appropriate amount of any of these packaged forms.

Tablets or capsules are preferred for oral administration, liquids are preferred for intravenous administration.

Methods of treatment

The compounds of the invention are particularly useful in the treatment of parkinsonism, depression, obesity, narcolepsy and drug abuse due to their significant ability to inhibit dopamine reuptake at a low incidence of their adverse side effects. These properties make the compounds of the present invention particularly useful in the treatment of parkinsonism, depression, obesity, narcolepsy and drug abuse, as well as other disorders susceptible to the ability of the compounds of the present invention to inhibit dopamine reuptake. Accordingly, the compounds of the invention may be administered to a living animal organism, including a human, to treat, attenuate, or eliminate any indication associated with, or a susceptible to, inhibition of dopamine reuptake inhibition. These include in particular parkinsonism, depression, obesity, narcolepsy and drug abuse. A suitable dosage range is from 0.1 to 500 milligrams per day, in particular 10 to 70 milligrams per day, administered one or two times daily depending upon the particular mode of administration, the dosage form employed, the indication of treatment, the subject and body weight, and from other reasons and experience of the doctor or veterinarian performing the treatment.

The following examples further illustrate the invention, but these examples are not to be construed as limiting.

Example 1

(-) - Anhydroecgonine methyl ester

(1R, 2R, 3S) -2-Carbomethoxy-3-benzoxytropane hydrochloride (100 g, 0.28 mol) was refluxed in 1000 mL of 1 M hydrochloric acid for 18 hours and then the solution was cooled on ice. The benzoic acid was removed by filtration and the filtrate was concentrated in vacuo. Trituration of the residue with ethanol and filtration afforded (1R, 2R, 3S) -3-hydroxy-tropane-2-carboxylate hydrochloride as a white crystalline solid which was dried and refluxed in phosphorus trichloride (50 ml) for two hours without further purification. The solution was concentrated in vacuo and absolute methanol (150 mL) was slowly added while cooling on ice. The solution was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was cooled with ice and made alkaline with sodium hydroxide solution (10 M, approximately 100 mL) followed by 5-fold extraction with diethyl ether. The combined organic phase was dried and concentrated in vacuo. An oil was obtained which, after distillation in vacuo (70-74 ° C, 1 mBar) gave the title compound as a clear oil.

Example 2 (1R, 2S, 3S) -2-carbomethoxy-3- (4-fluorophenyl) tropane and (1R, 2R, 3S) -2-carbomethoxy-3- (4-fluorophenyl) -propane

WgBr

>

In three narrow-necked reaction flasks with a mechanical stirrer, a powerful cooler and a pressure equalizer funnel,

Of 4-bromofluorobenzene (27.5 mL, 250 mmol) and magnesium trichloride (6.3 g, 260 mmol) in 250 mL of absolute diethylene prepared the Grignard reagent. The Grignard reagent solution was cooled to -20 ° C and a solution of (-) - anhydroecgonine methyl ester (21.7 g, 120 mmol) in 100 mL of absolute diethyl ether was added over 1/2 hour. The reaction mixture was stirred for 1 hour at -20 ° C and the reaction was cooled rapidly in one of the following two ways:

1) The reaction mixture was stirred into 250 ml of crushed ice and the aqueous phase was acidified by the addition of approximately 100 ml of 4M hydrochloric acid. The organic phase was removed and the aqueous phase was washed with 100 ml diethyl ether. The pH of the aqueous phase was made basic by the addition of 25% ammonium hydroxide solution, then the aqueous phase was saturated with sodium chloride and finally extracted three times with diethyl ether. The combined organic phase was dried and concentrated in vacuo to give an oil which was distilled under vacuum (150-160 ° C, 2 mBar). This method yielded a mixture of two stereoisomers (2S / 2R - 1/3) which was separated by column chromatography with a mixture of diethyl ether and pentane (1 + 1) + 1% triethylamine as eluent. The crude products were triturated in pentane to give (1R, 2S, 3S) -2-carbomethoxy-3- (4-fluorophenyl) tropane, white crystals of m.p. 91-92 ° C and (1R, 2R, 3S) -2-carbomethoxy-3- (4-fluorophenyl) tropane, white crystals of m.p. 65-66 [deg.] C.

2) The reaction mixture was cooled to -78 ° C and a solution of trifluoroacetic acid (20 mL, 250 mmol) in 50 mL diethyl ether was added over 10 min. The cooling bath was removed and when the temperature reached 0 ° C the mixture was stirred into 700 ml of water. The pH of this aqueous phase was adjusted to pH = 1 by addition of concentrated hydrochloric acid, followed by an aqueous phase procedure and purification in the same manner as described above. This method yielded a mixture of two stereoisomers (2S / 2R - 2/1).

- 40 The following substances were prepared in a similar manner:

(1R, 2R, 3S) -2-Carbomethoxy-3-benzyltropane and (1R, 2S, 3S) -2-cabomethoxy-3-benzyltropane, Method 2 only, (1R, 2S, 3S) -2-carbomethoxy- 3-Benzyltropane was obtained without contamination by the second isomer as an oil that crystallized at rest, with mp Mp 53-54 ° C.

(1R, 2R, 3S) -2-Carbomethoxy-3-benzyltropane was obtained by isomerizing the mixture as described in Example 3.

(1R, 2R, 3S) -2-Carbomethoxy-3- (4-chlorophenyl) tropane and (1R, 2S, 3S) -2-carbomethoxy-3- (4-chlorophenyl) tropane by method No.2. The two isomers did not separate but the mixture was isomerized as described in Example 3 (1R, 2R, 3S) -2-Carbomethoxy-3- (4-chlorophenyl) tropane, (1R, 2S, 3S) -2-carbomethoxy-3- (4-chlorophenyl) tropane, (1S, 2S, 3R) -2-carbomethoxy-3- (4-chlorophenyl) tropane and (1S, 2R, 3R) -2-carbomethoxy-3- (4- (chlorophenyl) tropane were prepared by Method No. 2. The two sets of pairs of enantiomers were not separated, but the mixture was isomerized as described in Example 3.

(1R, 2R, 3S) -2-Carbomethoxy-3- (4-methylphenyl) tropane and (1R, 2S, 3S) -2-carbomethoxy-3- (4-methylphenyl) tropane were prepared by Method # 2. Both isomers did not separate but the mixture was isomerized as described in Example 3 of (1R, 2S, 3S) -2-Carbomethoxy-3- (2-naphthyl) tropane and (1R, 2R, 3S) -2- carbomethoxy-3 (2-naphthyl) tropane was prepared by Method # 2. The Grignard reagent was prepared by adding a mixture of one equivalent of 2-bromonaphthalene and 1,2-dibromoethane in diethyl ether to a refluxing suspension of two equivalents of magnesium. Both products were white crystalline materials, m.p. 79-80 ° C, respectively. M.p. 86-87 ° C.

(1R, 2R, 3S) -2-Carbomethoxy-3- (1-naphthyl) tropane and (1R, 2S, 3S) -2-carbomethoxy-3 (1-naphthyl) tropane hydrochloride, method No.2. The Grignard reagent was prepared by adding a mixture of one equivalent of 1-bromonaphthalene and 1,2-dibromoethane in diethyl ether to a refluxing suspension of two equivalents of magnesium. Both of the substances mentioned in

- 41 of the title, the first of which was a white crystalline substance, m.p. 133-135 ° C and the other was an amorphous substance.

(1R, 2S, 3S) -2-Carbomethoxy-3- (3,4-dichlorophenyl) tropane and (1R, 2R, 3S) -2-carbomethoxy-3- (3,4-dichlorophenyl) tropane by method No.2. Both: products are white crystalline solids, m.p. 69-70 ° C, respectively. 61-63 [deg.] C.

Racemic mixture of (1R, 2R, 3S) -2-carbomethoxy-3- (3,4-dichlorophenyl) tropane and its enantiomer of (1S, 2S, 3R) -2-carhomethoxy-3- (3,4-dichlorophenyl) tropane prepared from (±) -anhydroecgonine methyl ester as starting material by Method 2 followed by isomerization according to the method described in Example 3.

(1S, 2S, 3R) -2-Carbomethoxy-3- (3,4-dichlorophenyl) tropane was prepared by Method # 2. The compound was not isolated but isomerized by method # 3.

(1R, 2S, 3S) -2-Carbomethoxy-3- (4-phenyl-phenyl) tropane and (1R, 2R, 3S) -2-carbomethoxy-3- (4-phenyl-phenyl) tropane were prepared according to method no. second Both products were white crystalline materials with m.p. 130-132 ° C, respectively. Mp 95-96 ° C.

(1R, 2S, 3S) -2-Carbomethoxy-3- (4-t-butylphenyl) tropane and (1R, 2R, 3S) -2-carbomethoxy-3- (4-t-butylphenyl) tropane with prepared by method No.2. Both bean white crystalline products with m.p. 84-85 ° C, respectively. 83-84 DEG.

Example 3 (1R, 2R, 3S) -2-Carbomethoxy-3-benzyltropane hydrochloride

To a solution of (1R, 2S, 3S) -2-carbomethoxy-3-benzyltropane (5.6 g, 20.5 mmol) in absolute methanol (100 mL) was added a solution of sodium methanolate in methanol (2 M, 2 mL) and the mixture was refluxed for 16 hours. The reaction mixture was concentrated in vacuo, the residue was dissolved in diethyl ether and washed with water. The organic phase was dried a

- 42 concentrated in vacuo. The crude product was purified by column chromatography using a mixture of diethyl ether and pentane (1 + 1) + 1% triethylamine as eluent. (1R, 2R, 3S) -2-Carbomethoxy-3-benzyltropane was obtained as an oil. After dissolution of this product in diethyl ether, after addition of hydrochloric acid in diethyl ether, the title compound precipitated as white crystals of m.p. Mp 188-199 ° C.

Example d 4

2-carbomethoxy-3-tropanone

To a suspension of sodium hydride (3.2 g 80%, 107 mmol, pre-washed in cyclohexane) and dimethyl carbonate (9.13 mL, 108 mmol) in absolute cyclohexane heated to reflux temperature was added a solution of (±) -3-tropanone ( 6.9 g (50 mmol) in 50 mL absolute cyclohexane over 15 minutes. No hydrogen formation was seen, so 0.2 mL of methanol was added. The reaction mixture was stirred overnight at reflux temperature and after cooling to room temperature, 75 mL of water was carefully added. 40 g of ammonium chloride were added to the aqueous phase and the resulting mixture was extracted 8 times with methylene chloride. The combined methylene chloride phases were dried and concentrated in vacuo followed by column chromatography of the crude product using methylene chloride with increasing amounts (up to 10%) of methanol as eluent. Product containing fractions were concentrated in vacuo and the resulting oil was subjected to kugelrohr destillation (1 mbar, 120 ° C) to give the title compound as orange crystals, m.p. Mp 104-107 ° C.

Example 5

2-Carb omethoxy-3-hydroxypropane hydrochloride

N

COOMe / H

COOMe

OH

43 To a solution of 2-carbomethoxy-3-tropanone obtained in Example 4 (17 g, 85 mmol) in 750 mL of ethanol cooled to -35 ° C was added sodium borohydride (17 g, 450 mmol) and the mixture was stirring for 4 hours. The cooled solution was quenched by the slow addition of concentrated hydrochloric acid (40 mL) and the mixture was concentrated in vacuo. Water (400 mL) was added and the pH was adjusted to 3 by addition of concentrated hydrochloric acid. After washing the aqueous phase three times with diethyl ether, the pH was adjusted to 11 by addition of concentrated ammonium hydroxide and the aqueous phase was extracted three times with methylene chloride. Concentration in vacuo yielded an oil which was dissolved in ethanol followed by concentration in vacuo. Freeze-drying of the residue afforded the title compound as an amorphous substance.

(1S) -carbomethoxy-3-hydroxy-tropane, an amorphous solid, was prepared in a similar manner, starting from (1S) -2-carbomethoxy-3-propanone obtained by the separation described in J. Med. Chem., 37, 2007 (1994) from the compound obtained in Example 4.

Example 6

(1RS) -anhydroecgonine methyl ester, COOMo

M

OH

COOMe

A mixture of 2-carbomethoxy-3-hydroxy-tropane hydrochloride obtained in Example 5 (0.5 g, 2.1 mmol) and thionyl chloride (0.4 mL, 5.3 mmol) was stirred at 60 ° for 2 hours. C to give a clear solution. After cooling to room temperature, crushed ice was added and the pH was adjusted to 11 by addition of concentrated ammonium hydroxide. The mixture was extracted twice with methylene chloride, the solvent was removed in vacuo to give the title compound as an oil, which was then distilled at 1 mbar and 70-85 ° C.

(1S) -anhydroecgonine methyl ester, oil, was prepared in a similar manner, starting from the (1S) -carbomethoxy-3-hydroxy-tropane obtained in Example 5.

- 44 Example 7 (1R, 2R, 3S) -N-Normethyl-2-carbomethoxy-3- (3,4-dichlorophenyl) tropane

. A mixture of (1R, 2R, 3S) -2-carbomethoxy-3- (3,4-dichlorophenyl) tropane (8.7 g, 27 mmol) and 2,2,2-trichloroethyl chloroformate (14.6 mL, 106 mmol) in dry toluene (100 mL) was refluxed for 18 hours. The reaction mixture was concentrated in vacuo and to the residue was added methylene chloride, which was then washed with water. The organic phase was dried and concentrated in vacuo. The residue was dissolved in 75% aqueous acetic acid (60 mL). To the reaction mixture was added zinc powder (8.7 g). The mixture was then stirred at room temperature for 18 hours. Concentrated ammonium hydroxide (pH> 7) was added and the mixture was extracted twice with diethyl ether. The combined organic phase was dried under vacuum to give the title compound as an oil, which was used without further purification.

Example d8 (1R, 2R, 3S) -N-Normethyl-N- (tert-butoxycarbonyl) -2-carbomethoxy-3- (3,4-dichlorophenyl) tropane

A solution of (1R, 2R, 3S) -N-Normethyl-2-carbomethoxy-3- (3,4-dichlorophenyl) tropane (7 g, 22.3 mmol) and di-tert-butyl dicarbonate (7.7 mL, 33.6 mmol) in dry tetrahydrofuran (50 mL) was stirred for 1 hour at room temperature. The reaction was quenched by the addition of ice (100 mL). The mixture was extracted twice with diethyl ether and dried and concentrated in vacuo to give the title compound as an oil, which was used without further purification.

Example d 9 (1R, 2S, 3S) -2-Hydroxymethyl-3- (4-fluorophenyl) tropane

To a suspension of lithium aluminum hydride (0.8 g, 21 mmol) in diethyl ether (30 mL) at room temperature was slowly added a solution of (1R, 2S, 3S) -2-carbomethoxy-3- (4-fluorophenyl) tropane (5 g, 18 mmol) in 100 mL diethyl ether. The reaction was allowed to stir for 10 minutes and was quenched by the addition of 0.8 mL of water, 0.8 mL of sodium hydroxide (15%) and 2 mL of water. The aluminum reindeer was removed by filtration and the solvent was removed in vacuo to give an oil. The title compound precipitated upon trituration with pentane as white crystals of m.p. 79-80 ° C.

The following substances were prepared in a similar manner:

(1R, 2R, 3S) -2-Hydroxymethyl-3- (4-fluorophenyl) tropane, white crystals, m.p. Mp 169-170 ° C.

(1R, 2R, 3S) -2-Hydroxymethyl-3- (3,4-dichlorophenyl) tropane, white crystals,

mp 145-150 ° C.

(1R, 2R, 3S) -N-Normethyl-N- (tert-butoxycarbonyl) -2-hydroxymethyl-3- (3,4-dichlorophenyl) tropane, oil.

(1R, 2S, 3S) -2-Hydroxymethyl-3- (3,4-dichlorophenyl) tropane, white crystals, m.p. 83-89 [deg.] C.

Racemic mixture of (1R, 2R, 3S) -2-hydroxymethyl-3- (3,4-dichlorophenyl) tropane and its enantiomer of (1S, 2S, 3R) -2-hydroxymethyl-3- (3,4-dichlorophenyl) tropane, tt Mp 186-187 ° C.

(1S, 2S, 3R) -2-Hydroxymethyl-3- (3,4-dichlorophenyl) tropane, m.p. 179-184 ° C.

(1R, 2R, 3S) -2-Hydroxymethyl-3- (4-chlorophenyl) tropane, white crystals, m.p. 200-202 ° C.

Example 10 (1R, 2R, 3S) -2-Formyl-3- (3,4-dichlorophenyl) tropane

Cl Cl

To a solution of oxalyl chloride (2.3 mL) in absolute methylene chloride (60 mL) at -60 ° C was added a solution of dimethylsulfoxide (4 mL) in absolute methylene chloride (10 mL) over 10 minutes. The mixture was stirred for 10 minutes and then a suspension of (1R, 2R, 3S) -2-hydroxymethyl-3- (3,4-dichlorophenyl) tropane (7 g, 23.3 mmol) in absolute methylene chloride (400 mL) was added over 15 minutes. ml). The resulting mixture was stirred for 10 minutes. Triethylamine (17 mL, 0.12 mol) was then added and the mixture stirred for an additional 10 minutes. The reaction mixture was allowed to reach room temperature and was quenched by the addition of water (200 mL). The organic phase was washed twice with water, dried and concentrated in vacuo to give the title compound as white crystals of m.p. 131-135 [deg.] C.

The following substances were prepared in a similar manner:

Racemic mixture of (1R, 2R, 3S) -2-formyl-3- (3,4-dichlorophenyl) tropane and its enantiomer of (1S, 2S, 3R) -2-formyl-3- (3,4-dichlorophenyl) tropane, which was used without further purification.

(1S, 2S, 3R) -2-Formyl-3- (3,4-dichlorophenyl) tropane, which was used without further purification.

(1R, 2R, 3S) -2-Formyl-3- (4-chlorophenyl) tropane, which was used without further purification.

(1R, 2R, 3S) -N-Normethyl-N- (ZerZ-butoxycarbonyl) -2-formyl-3- (3,4-dichlorophenyl) tropane, an oil which was used without further purification.

The following compounds were prepared in a similar manner, but the intermediate aldehyde was not isolated because of the risk of isomerization from the (1R, 2S, 3S) isomer to the (1R, 2R, 3S) isomer. Instead of warming the reaction mixture to room temperature and adding water to quench the reaction, an appropriate amount of excess hydroxylammonium reindeer (3 equivalents) was added to the reaction mixture, and the mixture was allowed to reach room temperature.

- 47 room temperature at which it was then stirred for 18 hours. The reaction mixture was washed twice with water and the organic phase was dried and concentrated in vacuo.

(R, 2S, 3S) -3- (3,4-Dichlorophenyl) tropane-2-aldoxime. Isolation by filtration of the reaction mixture as a syn / anti isomer mixture 20% + 80% (judged by NMR), without identifying the identity of the two isomers. The product was not further purified, white crystals, m.p. Mp 248-252 ° C.

(R, 2S, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-methyl-aldoxime. Concentration of the methylene chloride phase gave an oil which was subjected to column chromatography using a 4: 1 + 1 mixture of methylene chloride, acetone and methanol as eluent. This afforded the title compound as white crystals of m.p. 98-100 ° C.

(1R, 2S, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-benzyl-aldoxime hydrochloride. Concentration of the methylene chloride phase yielded an oil which was subjected to column chromatography using ethyl acetate as eluent to give an oil again. Finally, this oil was dissolved in a small volume of diethyl ether and a solution of hydrochloric acid in diethyl ether was added to give the title compound as white crystals of m.p. Mp 196-197 ° C.

Example d 11 (1R, 2R3) -3- (3,4-Dichlorophenyl) tropan-2-aldoxime

Cl Cl

To a solution of (1R, 2S, 3S) -2-formyl-3- (3,4-dichlorophenyl) tropane (6.9 g, 23 mmol) in methanol (100 mL) was added sodium carbonate (4 g) and hydroxylammonium chloride (2.6 g, 37 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with water. The crude product was isolated by filtration and recrystallized first in a mixture of ethanol and water (1 + 1) and then in 99% ethanol to give the title compound (mixture of syn / anti isomers - about 1 + 2) as white crystals with tt Mp 230-235 ° C.

- 48 In a similar way, the following substances were obtained:

(1R, 2R, 3S) -3- (4-Chlorophenyl) tropane-2-O-aldoxime, white crystals, m.p. Mp 220-222 ° C.

(1R, 2R, 3S) -3- (4-Chlorophenyl) tropane-2-O-methylaldoxime hydrochloride, white crystals, m.p. Mp 90-93 ° C.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-aldoxime, oil.

Racemic mixture of (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime and its enantiomer (1S, 2S, 3R) -3- (3,4-dichlorophenyl) tropane- 2-O-methyl-aldoxime, m.p. M.p. 172-178 ° C.

(1S, 2S, 3R) -3- (3,4-Dichlorophenyl) tropane-2-O-methyl-aldoxime, m.p. Mp 123-130 ° C.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-benzyl-aldoxime, white crystals, m.p. Mp 161-163 ° C.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-phenyl-aldoxime, H 2 SO 4, m.p. 100-102 ° C.

(1R, 2R, 3S) -N-Normethyl-N- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxone, an oil which was used without further purification.

(1R, 2R, 3S) -N-Normethyl-N- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxime, an oil which was used without further purification.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O- (2-propynyl) aldoxium hydrochloride, white crystals, m.p. &Lt; 100 ° C.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O- (2-propenyl) -aldoxime hydrochloride, white crystals, m.p. 131-133 [deg.] C.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O- (2-methylpropyl) -aldoxium hydrochloride, white crystals, m.p. Mp 161-163 ° C.

49 (1R, 2R, 3S) -3- (3,4-Dichloro-phenyl) -propanol-2-O-cyclopropylmethyl-aldoxime hydrochloride, white crystals, m.p. Mp 173-175 ° C.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-ethyl-aldoxime hydrochloride, white crystals, m.p. &Lt; 110 ° C.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O- (1,1-dimethylethyl) -aldoxime hydrochloride, white crystals, m.p. Mp 213-215 ° C.

(1R, 2R, 3S) -3- (4-Methylphenyl) tropane-2-O-methyl-aldoxime hydrochloride, white crystals, m.p. <95 ° C (hygroscopic).

Re (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-methyl-aldoxime was prepared as follows:

An acid solution (3.25 mmol) was added to a solution of (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime (1 g, 3.0 mmol) in 96% ethanol ( 5 ml) and the mixture was stirred at room temperature. If no precipitation was observed after 18 hours, the mixture was concentrated in vacuo and the concentrated mixture was allowed to precipitate in the refrigerator. The crystalline product was isolated by filtration and washed with small amounts of ice-cold 96% ethanol.

The salt was recrystallized from water or isopropanol.

The following salts of (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime were obtained:

maleate: white crystals, m.p. (H 2 O) 140-142 ° C citrate white crystals, m.p. (isopropanol) 143-144 ° C malonate: white crystals, m.p. (isopropanol) 116-118 ° C fumaran: white crystals, m.p. (H 2 O) 158-159 ° C

H2SO4 white crystals, t, t. (H 2 O) 84-87 ° C recrystallization from H 2 O yields the bivalent salt with a small amount of hydrogen sulfate. Precipitation of reindeer from isopropanol gives the bisulfate with m.p. Mp 161-163 ° C. white crystals, m.p. (H 2 O) 74-75 ° C.

HCl

- 50 Example 12 (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-ethoxycarbonylmethyl-aldoxime hydrochloride

A solution of (1R, 2R, 3S) -2-formyl-3- (dichlorophenyl) tropane (1 g), O- (2-acetoxy) -2-hydroxylammonium chloride (0.5 g) and concentrated hydrochloric acid in ethanol (1 g). ml) was refluxed for 5 hours. This was followed by stirring at room temperature for 18 hours. The mixture was concentrated in vacuo and the residue triturated with isopropanol. The title compound was isolated by filtration as white crystals of m.p. Mp 220-222 ° C.

The following substances were prepared in a similar manner:

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime hydrochloride, white crystals, m.p. Mp 193-195 ° C.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O- (1-ethoxycarbonyl-1,1-dimethylmethyl) aldoxime hydrochloride, white crystals, m.p. Mp 213-215 ° C.

(1R, 2R, 3S) -3- (4-Chlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime hydrochloride, white crystals, m.p. 202-203 ° C.

(1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-carboxymethyl-2-aldoxime hydrochloride. It was obtained together with (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methoxycarbonylmethylaldoxime hydrochloride after refluxing for 1 hour. White crystals, m.p. Mp 158-160 ° C.

Example 13 (1R, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime hydrochloride

BocN _ν, ΟΗΝΟΜβ

Λ ^ -Q-a

Cl

CHNOMe

Cl

Cl

- 51 A mixture of (1R, 2R, 3S) -N-Normethyl-N- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) tropane-O-methyl-aldoxime (1.3 g, 3.1 mmol) ) and trifluoroacetic acid (10 mL) in absolute methylene hydrochloride (10 mL) was stirred for 1 hour. Then ice and methylene chloride (50 ml) were added and the pH of the mixture was adjusted to 10 by addition of 4M sodium hydroxide. The organic phase was dried and concentrated in vacuo. This gave an oil which was purified by column chromatography with a mixture of methylene chloride, methanol and 25% ammonium hydroxide (90 + 10 + 1). The fractions containing the product were concentrated in vacuo. The obtained oil was dissolved in a small amount of diethyl ether and a solution of hydrochloric acid in diethyl ether was added. The title compound was obtained as white crystals with m.p. Mp 226-230 ° C.

In a similar way, the following substances were obtained:

(1R, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxine hydrochloride, m.p. 70-72 [deg.] C.

(1R, 2R, 3S) -N-Normethyl-3- (4-chlorophenyl) tropane-2-aldoxime malonate, m.p. 70-75 [deg.] C.

(1R, 2R, 3S) -N-Normethyl-3- (4-chlorophenyl) tropane-2-O-methyl-aldoxime H2SO4.

Example 14

Syn- and anti-isomers of (1R, 2R, 3S) and (1S, 2S, 3R) -3- (3,4-dichlorophenyl) tropane-2-O-methylaldoxime.

Formation of (1R, 2R, 3S) and (1S, 2S, 3R) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime by reaction of the corresponding 2-formyl compound and methoxyammonium chloride as described in Example 12 provides a mixture of the syn- and anti-isomers resulting from the kinetic regulation of the product and the isomerization of the originally formed mixture. The kinetic mixture favors the anti-isomer (&gt; 90%) and the equilibrium mixture contains 7/3 anti / syn. This anti / syn equilibrium is catalyzed by acid and the equilibrium mixture can be easily obtained by heating the aqueous material solution at 100 ° C for three hours at pH 4. Column chromatography of the equilibrium mixture using toluene, ethyl acetate and triethylamine (2 + 1) + 2% as eluent to give the syn-isomer as an oil which can be distilled in the kugelrohr destillation without isomerization.

Claims (16)

Use of a compound of the general formula N H R R H R H H H icb of any mixture, or a pharmaceutically acceptable salt thereof; where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; R 6 is CH = NOR ', wherein R' is hydrogen, or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted with COOH, COO-alkyl, COO-cycloalkyl, or phenyl, which may be mono- or polysubstituted with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino and nitro; and R ⁴ is phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, beteroaryl and aryl; 3,4-methylenedioxyphenyl; benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; heteroaryl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, 53 alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or naphthyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl for the manufacture of a medicament for treating a disorder or disease an animal organism, including a human, that responds to inhibition of reuptake of monoamine neurotransmitters in the central nervous system. 2. Use of a compound of the general formula, any mixture thereof, or a pharmaceutically acceptable salt thereof; where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; is CH = NOR ', wherein R' is hydrogen, or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted with COOH, COO-alkyl, COO-cycloalkyl, or phenyl, which may be single or multiply substituted with substituents selected from the group consisting of hydrogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, and nitro; and R ⁴ is phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cyclalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroalkyl and aryl; 54 3,4-methylenedioxyphenyl; benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or t naphthyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl, for the manufacture of a medicament for treating a disorder or disease an animal organism, including a human, that responds to inhibition of dopamine reuptake in the central nervous system. . 3. Use of a compound of the general formula, any mixture thereof, or a pharmaceutically acceptable salt thereof; where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; R ³ is CH = NOR ', wherein R' is hydrogen, or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted with COOH, COO-alkyl, COO-cycloalkyl, or phenyl, which may be mono- or polysubstituted with substituents selected from the group consisting of hydrogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, and nitro; and R ⁴ is phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroalkyl and aryl; 3,4-methylenedioxyphenyl; benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryhi; heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryhx and aryl; or naphthyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitroscypine, heteroaryl and aryl, for the manufacture of a medicament for the treatment of parkinsonism, depression , obesity, narcolepsy, or drug addiction; drug abuse. Use according to claims 1, 2 and 3, wherein the substance used is 3- (3,4-dichlorophenyl) tropan-2-aldoxime, 3- (3,4-Dichlorophenyl) tropane-2-O-methyl-aldoxime, 3- (3,4-Dichlorophenyl) tropane-2-O-benzyl-aldoxime, 3- (3,4-Dichlorophenyl) tropane-2-O-ethoxycarbonylmethyl-aldoxime, 3- (3,4-Dichlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime, 3- (3,4-Dichlorophenyl) tropane-2-O- (1-ethoxycarbonyl-1,1-dimethylmethyl) -aldoxime, 3- (3,4-Dichlorophenyl) tropane-2-O-carboxymethyl-2- aldoxmt, N-normethyl-3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime, or 56 N-Non-methyl-3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxime, or a pharmaceutically acceptable addition salt thereof. Use according to claims 1, 2 and 3, wherein the substance used is (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropan-2-aldoxime, (1R, 2R, 3S) -3- (3 4-dichlorophenyl) tropane-2-O-benzyl-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) -thiopan-2-O-ethoxycarbonylmethyl-aldoxime, (1R, 2R, 3S) - 3- (3,4-dichlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O- (1-ethoxycarbonyl-1,1) -dimethylmethyl) aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-carboxymethyl-2-aldoxime, (1R, 2R, 3S) -N-normethyl-3- (3,4-Dichlorophenyl) tropane-2-O-methyl-aldoxime or (1R, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) tropa-2-O-benzyl-aldoxime, or a pharmaceutically acceptable addition thereof. Use according to claims 1, 2 and 3, wherein the substance used is (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime, or a pharmaceutically acceptable addition salt thereof. Use according to claim 6, wherein the substance used is the anti-isomer (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime, the syn-isomer (1R, 2R, 3 S) -3- (3,4-dichlorophenyl) tropan-2-O-methyl-aldoxime, a mixture thereof, or a pharmaceutically acceptable addition salt thereof. A compound of the formula any mixture thereof, or a pharmaceutically acceptable salt thereof; where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; 57 is CH = NOR ', wherein R' is hydrogen, or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted with COOH, COO-alkyl, COO-cycloalkyl, or phenyl, which may be mono- or polysubstituted with substituents selected from the group consisting of hydrogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, and nitro; and R ⁴ is phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroalkyl and aryl; 3,4-methylenedioxyphenyl; benzyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroalkyl and aryl; heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, beteroaryl and aryl; or naphthyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl. The compound of Claim 8 which is 3- (3,4-dichlorophenyl) tropan-2-aldoxime, 3- (3,4-dichlorophenyl) tropan-2-O-methyl-aldoxime, 3- (3,4-dichlorophenyl) tropan-2-O-benzyl-aldoxime, 3- (3,4-dichlorophenyl) tropan-2 -O-ethoxycarbonylmethyl-aldoxime, 3- (3,4-dichlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime, 58- 3- (3,4-dichlorophenyl) tropane-2-O- (1-ethoxycarbonyl-1,1-dimethylmethyl) -aldoxime, 3- (3,4-dichlorophenyl) tropane-2-O-carboxymethyl- 2-aldoxime, N-normethyl-3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime or N-normethyl-3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxime, or a pharmaceutically acceptable addition salt thereof. The compound of claim 8 which is (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropan-2-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropan-2-O-benzyl-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-ethoxycarbonylmethyl-aldoxime, (1R, 2R, 3S) -3- (3 4-Dichlorophenyl) tropane-2-O-methoxycarbonylmethyl-aldoxime, (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O- (1-ethoxycarbonyl-1,1-dimethyl-methyl) Aldoxime, (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropane-2-O-carboxymethyl-2-aldoxime, (1R, 2R, 3S) -N-Normethyl-3- {3,4 -dichlorophenyl) tropane-2-O-methyl-aldoxime or (1R, 2R, 3S) -N-normethyl-3- (3,4-dichlorophenyl) tropane-2-O-benzyl-aldoxime, or a pharmaceutically acceptable addition salt thereof . The compound of claim 8 which is (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime, or a pharmaceutically acceptable addition salt thereof. The compound of claim 11 which is the (1R, 2R, 3S) -3- (3,4-dichlorophenyl) tropane-2-O-methyl-aldoxime anti-isomer, the syn (1R, 2R, 3S) - 3- (3,4-Dichlorophenyl) tropane-2-O-methyl-aldoxime, a mixture thereof, or a pharmaceutically acceptable addition salt thereof. A process for the preparation of compounds according to claim 8, comprising the step of wherein the compound of formula R is an enantiomer thereof, or mixtures thereof, wherein R is as defined in claim 8 and R ^{2 is a} carboxylic ester, or wherein R ² is as R ² in claim 8, 59 reacts with a compound of formula R ⁴ -A, wherein R ⁴ is as defined in claim 8 and A is any type of reactive group suitable for forming a carbanion as a counterpart thereof, e.g. Li, MgX, where X is halogen and CuLi in a Michael-like addition reaction. type 1,4 and wherein when R * ² is a carboxylic ester, the conversion of the obtained compound to the compound of claim 8 is carried out by conventional methods A pharmaceutical composition comprising an effective amount of a compound according to claim 8, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent. A method of treating a disorder or disease of a living animal organism, including a human, susceptible to dopamine reuptake inhibition comprising administering to the living animal organism, including a human, an effective amount of a compound of any mixture thereof, or a pharmaceutically acceptable salt thereof; where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; R ² is CH = NOR ', wherein R' is hydrogen, or alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or alkyl, all of which may be substituted with COOH, COO-alkyl, COO-cycloalkyl, or phenyl, which may be mono- or polysubstituted with substituents selected from the group consisting of hydrogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, and nitro; and R 60 is phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroalkyl and aryl; 3,4-methylenedioxyphenyl; benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitroslupmy, heteroaryl and aryl; heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or naphthyl, which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl. The method according to claim 16, wherein the treatment of parkinsonism, obesity, narcolepsy or drug addiction or drug addiction is treated. drug addiction.